Therapeutic activation of AMPK for the aging right heart

摘要/项目摘要 此应用程序的总体目标是为 Bruns 博士提供科学和职业生涯 为在心脏衰老领域取得成功的独立研究事业而发展， 特别关注右心室。心力衰竭（HF）是一个主要的公共卫生问题 人口老龄化。在与年龄相关的左心衰竭以及其他临床情况中，右心衰竭 心室（RV）功能障碍是死亡率最强的预测因素。然而，尽管明确 右心功能与生存之间的联系，人们对右心功能随年龄的变化知之甚少。 这种知识差距强调了评估老化对房车的影响的必要性 开发针对右心室功能下降的治疗方法的长期目标。虽然没有房车- 存在定向疗法，流行病学数据和我们实验室的初步数据表明 AMP 激活蛋白激酶 (AMPK) 的激活可能通过新颖且直接的方式受益 对心脏收缩器官的作用。因此，本项目的全局假设是 衰老会加剧 RV 功能障碍，并且收缩装置介导的机制可以 被开发用于治疗衰老右心的新疗法。为了解决这个假设，我们提出 两个具体目标：1）评估年龄对两种右心衰竭模型的影响——孤立的 右心室压力超负荷和低压缺氧（肺动脉高压）引起的右心室 功能障碍，心血管衰老中一种非常重要且具有重要转化意义的疾病； 2) 确定 AMPK 的激活是否会减轻老年小鼠的心脏功能障碍，以及 发生这种情况的机制。我们将研究 AMPK 激活作为一种新颖的 RV 导向 使用遗传和药物方法治疗心脏衰老，促进 阐明心脏功能障碍的分子机制。导师团队和 为回答这个重要问题而聚集的职业发展将提供 衰老生物学、分子遗传学和肌丝力学方面的培训，这些是老年人的重要技能 作为一名独立的心脏衰老科学家的职业生涯。齐心协力，顺利完成本次活动 该提案将通过提供培训、指导和科学知识来推动科学独立性 在此基础上制定心脏衰老生物学领域成功的研究议程。

ABSTRACT/PROJECT SUMMARY The overarching goal of this application is to provide Dr. Bruns the scientific and career development for a successful independent research career in the field of cardiac aging, with a specific focus on the right ventricle. Heart failure (HF) is a major public health concern within aging populations. In age-related left-sided heart failure as well as other clinical contexts, right ventricular (RV) dysfunction is the strongest predictor of mortality. However, despite the clear link between right heart function and survival, very little is known about RV function with age. This knowledge gap underscores the need to assess the impact of aging on the RV with the long-term goal of developing therapeutics that target declining RV function. Although no RV- directed therapies exist, epidemiological data and preliminary data from our lab suggest that activation of AMP-activated protein kinase (AMPK) may be beneficial through novel and direct action on the cardiac contractile apparatus. Accordingly, the global hypothesis of this project is that aging exacerbates RV dysfunction, and contractile apparatus-mediated mechanisms can be exploited for novel therapies for the aging right heart. To address this hypothesis, we propose two specific aims: 1) to assess the impact of age on two models of right heart failure- isolated RV pressure overload and hypobaric hypoxia (pulmonary hypertension)-induced RV dysfunction, a highly significant and translationally important disease in cardiovascular aging; and 2) to determine if activation of AMPK attenuates cardiac dysfunction in aged mice, and the mechanisms by which this occurs. We will investigate AMPK activation as a novel RV-directed therapy in cardiac aging using both genetic and pharmaceutical approaches, facilitating the elucidation of molecular mechanisms underlying cardiac dysfunction. The mentorship team and career development assembled to answer this translationally important question will provide training in aging biology, molecular genetics, and myofilament mechanics, important skills for a career as an independent cardiac aging scientist. Together, successful completion of this proposal will propel scientific independence by providing the training, mentorship, and scientific guidance upon which to build a successful research agenda in the field of cardiac aging biology.